Endo180 (MRC2) Antibody-Drug Conjugate for the Treatment of Sarcoma.

Although the 5-year survival rates for sarcoma patients have improved, the proportion of patients relapsing after first-line treatment remains high, and the survival of patients with metastatic disease is dismal. Moreover, the extensive molecular heterogeneity of the multiple different sarcoma subtypes poses a substantial challenge to developing more personalized treatment strategies. From the IHC staining of a large set of 625 human soft-tissue sarcomas, we demonstrate strong tumor cell staining of the Endo180 (MRC2) receptor in a high proportion of samples, findings echoed in gene-expression data sets showing a significantly increased expression in both soft-tissue and bone sarcomas compared with normal tissue. Endo180 is a constitutively recycling transmembrane receptor and therefore an ideal target for an antibody-drug conjugate (ADC). An anti-Endo180 monoclonal antibody conjugated to the antimitotic agent, MMAE via a cleavable linker, is rapidly internalized into target cells and trafficked to the lysosome for degradation, causing cell death specifically in Endo180-expressing sarcoma cell lines. In a sarcoma tumor xenograft model, the Endo180-vc-MMAE ADC, but not an isotype-vc-MMAE control or the unconjugated Endo180 antibody, drives on-target cytotoxicity resulting in tumor regression and a significant impairment of metastatic colonization of the lungs, liver and lymph nodes. These data, together with the lack of a phenotype in mice with an Mrc2 genetic deletion, provide preclinical proof-of-principle evidence for the future development of an Endo180-ADC as a therapeutic strategy in a broad range of sarcoma subtypes and, importantly, with potential impact both on the primary tumor and in metastatic disease.

Optical Molecular Imaging of Inflammatory Cells in Interventional Medicine-An Emerging Strategy.

The optical molecular imaging of inflammation is an emerging strategy for interventional medicine and diagnostics. The host's inflammatory response and adaptation to acute and chronic diseases provides unique signatures that have the potential to guide interventions. Thus, there are emerging a suite of molecular imaging and sensing approaches for a variety of targets in this area. This review will focus on two key cellular orchestrators that dominate this area, neutrophils and macrophages, with recent developments in molecular probes and approaches discussed.

Solid-phase synthesis of biocompatible N-heterocyclic carbene-Pd catalysts using a sub-monomer approach.

Taking inspiration from the assembly of so-called peptoids (N-alkylglycine oligomers) we present a new synthetic methodology whereby N-heterocyclic carbene (NHC) based Pd ligands were assembled using a sub-monomer approach and loaded with Pd via solid-phase synthesis. This allowed the rapid generation a library of NHC-palladium catalysts that were readily functionalised to allow bioconjugation. These catalysts were able to rapidly activate a caged fluorophore and 'switch-on' an anticancer prodrug in 3D cell culture.